The objective of this proposal is to evaluate novel approaches for the treatment of melanoma through the molecular targeting of essential signaling pathways. To accomplish this translational objective, we have performed preclinical studies to identify and validate potential candidate targets in cellular proliferative and survival pathways, and based on these results we propose to conduct a scries of clinical trials to determine the efficacy and safety of inhibiting these pathways in patients with advanced melanoma. Overall, the goal of the first 2 specific aims is to capitalize on the recent discovery that the majority of human melanomas are associated with an activating mutation in BRAF and to selcct promising new agents which target the Raf pathway. For the first clinical trial, we have selected BAY 43-9006, a small molecule inhibitor of the Raf family of protein kinases to evaluate in a phase lI study in patients with metastatic melanoma. In specific aim 2, correlative laboratory studies will investigate the ability of BAY 43-9006 to inhibit its specific molecular target, Raf kinase, and we will assess whether the degree of inhibition of the RAF/MEK/ERK cascade in tumor tissue and surrogate tissues correlates with clinical response. Further studies will determine the relationship between clinical response to BAY 43-9006 and the mutational status of BRAF in the tumor samples and pharmacokinetic and pharmacodynamic analyses of BAY 43-9006 will be performed to determine kinetic characteristics that are effective in target inhibition. In specific aim 3, we will further investigate the role of survival pathways in melanoma by conducting preclinical and clinical studies to determine whether the PI3-Kinase/Akt/TOR survival pathway represents an additional site for therapeutic intervention in melanoma. While the primary objective of this proposal is therapeutic, that is, identifying safe and beneficial treatments for patients with melanoma, we anticipate accumulating further insights into understanding the basic biology of melanoma and signaling pathways as a byproduct of these preclinical and clinical studies.